Cigna Medical Coverage Policy

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1 Cigna Medical Coverage Policy Subject Stem-Cell Transplantation for Sickle Cell Disease and Thalassemia Major Table of Contents Coverage Policy... 1 General Background... 1 Coding/Billing Information... 5 References... 6 Effective Date... 7/15/2014 Next Review Date... 7/15/2015 Coverage Policy Number Hyperlink to Related Coverage Policies Donor Lymphocyte Infusion Genetic Testing for Hemoglobinopathies Transplant Donor Charges Umbilical Cord Blood Banking INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna companies. Coverage Policies are intended to provide guidance in interpreting certain standard Cigna benefit plans. Please note, the terms of a customer s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Proprietary information of Cigna. Copyright 2014 Cigna Coverage Policy Cigna covers myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)- matched donor (i.e., at least five of six match of the HLA-A, HLA-B, and HLA- DRB1 antigens) as medically necessary for the treatment of a child or young adult at increased risk of complications of sickle cell disease (SCD) or thalassemia major. Cigna does not cover non-myeloablative allogeneic HSCT for a child or young adult with SCD or thalassemia major because it is considered experimental, investigational or unproven. Cigna does not cover HSCT for an adult with SCD or thalassemia major because it is considered experimental, investigational or unproven. General Background Hemoglobinopathies are a group of rare, inherited disorders involving abnormal structure of the hemoglobin molecule. Several hundred unusual hemoglobins have been identified. Clinically significant variants include hemoglobin S-C disease, sickle cell anemia, various types of thalassemia, hemoglobin C, and hemoglobin E. (National Institutes of Health [NIH], 2013; Chiu, 2005; Sickle Cell Disease Association of America [SCDAA], 2014). Stem-Cell Transplantation Page 1 of 9

2 Stem-cell transplantation refers to transplantation of hematopoietic stem cells (HSCs) from a donor into an individual. HSC transplantation (HSCT) can be either autologous (using the individual s own stem cells) or allogeneic (using stem cells from a donor). In allogeneic HSCT, it is preferable for donors to have a human leukocyte antigen (HLA) type that is identical to the recipient. Matching is performed on the basis of variability at three or more loci of the HLA gene (e.g., HLA- A, HLA-B, HLA-DRB1). As HLA variability increases, transplant-related morbidity and mortality, including graft rejection and graft-versus-host disease, also increase. Although considered a standard approach for the treatment of malignant disease, HSCT with the use of haploidentical donors remains a subject of ongoing clinical trials. There are limited data to support the safety and effectiveness of a haploidentical donor for the treatment of sickle cell disease or thalassemia major. Sickle Cell Disease (SCD): SCD encompasses many sickling syndromes caused by abnormal sickle hemoglobin. The most common are sickle cell anemia (Hb SS), sickle-hemoglobin C disease (Hb SC), sicklebeta plus thalassemia, and sickle-beta zero thalassemia (NIH, 2013). The disease follows a variable clinical course which may include complications such as severe anemia, painful sickle cell crises, organ damage due to iron overload, acute chest syndrome, refractory pain, stroke, and premature death. Accepted treatment options include chronic blood transfusions, hydroxyurea, and allogeneic HSCT for children and young adults at risk for complications of the disease. Myeloablative Allogeneic HSCT: Myeloablative allogeneic HSCT is the only potentially curative treatment option for selected individuals with sickle cell disease or thalassemia major (Novelli, 2011; Bhatia, 2008; Krishnamurti, 2008). HSCT involves replacing the deformed red blood cells and the cells that produce them with normal cells from a healthy donor. Research to date has demonstrated that successful engraftment of normal donor hematopoietic stem cells prevents additional pathological effects of SCD. Full donor chimerism is not necessary to achieve this effect (Iannone, 2005; Krishnamurti, 2008). The optimal timing for marrow transplantation in the course of SCD remains uncertain, in part, because of the unpredictable nature and clinical heterogeneity of the disease. Patient selection criteria continue to evolve; however, children and young adults, generally before the age of 21 years are considered the most appropriate candidates. Indications for HSCT have been determined from prognostic factors derived from studies of the natural history of SCD. The most common indications for which patients with SCD have undergone HSCT are a history of stroke, recurrent acute chest syndrome, or frequent vaso-occlusive episodes (Novelli, 2011). Children and young adults who have severe complications (e.g. stroke, recurrent acute coronary syndrome [ACS], refractory pain) and have a human-leukocyte antigen (HLA)-matched donor are the best candidates for transplantation (Panepinto, 2007). Current research is focused on improving the applicability of HSCT to a greater proportion of patients with SCD by the development of novel conditioning regimens minimizing myeloablation and the use of novel sources of hematopoietic stem cells such as umbilical cord blood (Novelli; 2011). Literature Review Oringanje et al. (2013) performed a systematic review to determine whether stem-cell transplantation can improve survival, and prevent symptoms and complications associated with sickle cell disease. Data from randomized controlled and quasi-randomized studies were lacking; therefore, no conclusions could be made. The authors note that this systematic review identified the need for a multicenter randomized controlled trial assessing the benefits and possible risks of HSCT comparing sickle status and severity of disease in an individual with SCD. However, several case series, retrospective reviews, and registry analyses have demonstrated improved overall- and event-free survival with allogeneic HSCT, primarily in children 18 years (Dallas, 2013; Bernauldin, 2007; Panepinto, 2007; Locatelli, 2005). Five and six-year probabilities of disease-free-(dfs), and overall survival (OS) were 85% 86%, and 93% 97%, respectively (Dallas, 2013; Novelli, 2011; Bernauldin, 2007; Panepinto, 2007). In the retrospective analysis by Dallas et al. (2013) involving 22 children with sickle cell disease who underwent an allogeneic HSCT, median follow-up was 9.0 years, with an OS of 93% and a recurrence/graft failure rate of 0%, for those using matched-related donors. For those undergoing haploidentical allogeneic HSCT, median follow-up was 7.4 years, with an OS of 75%, DFS of 38%, and disease recurrence of Page 2 of 9

3 38%. Although limited by uncontrolled study design and small patient numbers, data suggest an improved overall survival (OS) with allogeneic hematopoietic stem-cell transplantation (HSCT). Summary of Myeloablative Allogeneic HSCT for Sickle Cell Disease (SCD): Although data are not robust, myeloablative allogeneic HSCT is considered an appropriate treatment option for selected children and young adults at high risk of complications of SCD. There are scarce data in the published, peer-reviewed scientific literature regarding safety and effectiveness in the adult population and at this time the role of myeloablative allogeneic HSCT for has not been established for this indication. Non-Myeloablative Allogeneic HSCT for SCD: Toxicity of myeloablative conditioning regimens and the finding that mixed chimerism can cure SCD have prompted recent studies using reduced toxicity conditioning regimens that do not cause ablation of hematopoiesis. At present, study populations include very small numbers of adults and children who have evidence of organ damage from vaso-occlusion or iron overload as a result of chronic transfusion therapy. Mortality related to graft-versus-host disease and graft rejection continues to be a complication related to this therapy. Published reports have confirmed improved safety, but the majority of these transplants are unsuccessful because of graft failure (Horwitz, 2007). Although investigations are continuing, it has been difficult to identify a regimen that is sufficiently immunosuppressive to ensure stable engraftment of donor cells while continuing to meet the objective of reduced toxicity. Literature Review Outcomes of several uncontrolled trials (total n=19) suggest that donor chimerism is possible in a majority of patients (Krishnamurti, 2008; Horwitz, 2007; Horan, 2005; Iannone, 2003). However, controlled clinical trial data are lacking, study populations are very limited, and effect on overall health outcomes is unknown. Krishnamurti (2008) evaluated outcomes for seven patients (median age eight years) with severe SCD who underwent allogeneic HSCT with reduced-intensity conditioning. At one year post transplantation six of seven patients had mixed donor chimerism. At a follow-up of years after transplantation, all patients were alive, off immunosuppression, and six of seven patients had no laboratory or clinical evidence of disease. Horwitz et al. (2007) reported the outcomes of two adult patients with SCD who underwent total-body irradiation followed by fludarabine-based nonmyeloablative conditioning and allogeneic HSCT. Both patients achieved complete donor chimerism, had normal blood counts and were on no immunosuppressive drugs. Horan et al. (2005) reported the results of four consecutive patients who received allogeneic HSCT with nonmyeloablative conditioning. Three patients had SCD (two patients had Hb SS; one patient had Hb C), and one patient had thalassemia major. Donors were human leukocyte antigen (HLA)-identical siblings in all cases. At three months post-transplantation, all patients had evidence of donor myeloid chimerism (range %); however, post-transplantation immunosuppression was discontinued and graft rejection occurred in three recipients. At 27 months follow-up, one patient was doing well, with full donor chimerism. One patient received a second HSCT for graft failure and died at 52 days post-hsct due to pneumonia and intractable heart failure. The other patients remained alive but without significant donor chimerism. Summary of Non-Myeloablative Allogeneic HSCT for SCD: The ability to draw conclusions regarding the effectiveness of this therapy is limited by small study size, use of heterogeneous conditioning regimens, and study design. Although promising and a subject of ongoing research, the role of nonmyeloablative conditioning and allogeneic HSCT has not yet been established for this indication. Thalassemia: Thalassemia is a hereditary anemia resulting from defects in hemoglobin production. These defects result in low levels of hemoglobin being produced and excessive destruction of red blood cells. There are two types of thalassemia, alpha and beta, depending on which of the two hemoglobin chains is involved. Alpha and beta thalassemia have both mild (i.e., minor) and severe (i.e., major) forms; the severity of the disease depends on the number and combination of genes affected. Because individuals with thalassemia minor variants have few physical symptoms and a normal lifespan is expected, HSCT is not considered an appropriate treatment option. The severe form of this disease is known as beta thalassemia major, Cooley s anemia, thalassemia major or Mediterranean anemia. Thalassemia major requires frequent, lifelong blood cell transfusions and folate supplements; the effects of iron overload may damage the heart, liver and endocrine systems. Without treatment, children with the severe form of the disease usually do not live beyond early childhood; however, Page 3 of 9

4 individuals with successfully treated thalassemia may live until their forties or beyond (National Heart, Lung, and Blood Institute [NHLBI], 2012). Myeloablative Allogeneic Hematopoietic Stem-Cell Transplantation (HSCT) for Thalassemia: Allogeneic HSCT is considered a potentially curative therapy for selected individuals with thalassemia major who have an appropriate donor (Holstein, 2011; Hongeng, 2006; Jaing, 2005). Data strongly suggest that the optimal timing of HSCT of an individual with a human leukocyte antigen (HLA)-identical sibling donor is at a very early age (Yesilipek, 2007). HSCT is associated with a non-negligible risk of transplantation-related mortality and morbidity which must be taken into account, considering the relevant improvements achieved with conventional therapy (Locatelli, 2005). The outcome of allogeneic HSCT using an HLA-identical family donor is largely dependent on the age of the recipient as well as on pretransplant parameters reflecting the degree of organ damage from iron overload (Resnick, 2007). Results with HSCT are generally better if no iron overload or organ damage is present and the patient has received a minimal number of erythrocyte transfusions (Smiers, 2010). Literature Review For individuals with good-risk disease with an HLA-compatible sibling donor, the probability of disease-free survival (DFS) is 80 90%. In children who do not have liver disease and have received regular chelation therapy, the probability of survival with transfusion independence is over 90% (Holstein, 2011; La Nasa, 2005; Locatelli, 2005). Worse results have been obtained in high-risk individuals where the probability of DFS is approximately 58% when transfusion independence after the allograft is achieved (La Nasa, 2005). Adults with thalassemia have more advanced disease and treatment-related organ complications, mainly because of prolonged exposure to iron overload. Adults generally have a worse outcome than children; their probabilities of overall survival (OS) and DFS are 65% 66% and 62% 65%, respectively (Smiers, 2010, Locatelli, 2005). Summary of Myeloablative Allogeneic HSCT for Thalassemia: Although data are not robust, myeloablative allogeneic HSCT is potentially curative for thalassemia major and is an accepted treatment option for selected children and young adults. There are scarce data in the published peer-reviewed scientific literature regarding the safety and effectiveness of myeloablative HSCT for the treatment of adults with thalassemia major. The role of this therapy has not yet been established for this indication. Non-Myeloablative Allogeneic HSCT for Thalassemia: There is insufficient evidence in the published, peerreviewed scientific literature regarding the feasibility of using non-myeloablative preparative regimens for patients with thalassemia. It has been considered essential to administer full myeloablative conditioning regimens for transplantation to ablate the abnormal host bone marrow. Disease recurrence and graft-versushost disease continue to be a source of morbidity and mortality following this therapy. Non-myeloablative regimens remain under clinical evaluation, with short post-transplantation follow-up times. Literature Review Resnick et al. (2007) reported the results of a cohort of 20 patients who underwent reduced toxicity fludarabinebased conditioning followed by allogeneic HSCT using matched-related and unrelated donors. Median patient age was 5.6 years. With a median follow-up of 39 months, 16 of 20 patients had sustained engraftment and were transfusion independent. The overall survival and thalassemia-free survival were 100% and 80%, respectively, at a median follow-up of 39 months. Larger cohorts of patients and prospective clinical trials are required to confirm the benefits of this approach as a possible better alternative to the existing protocols. Summary of Non-Myeloablative HSCT for Thalassemia Data are lacking to support the safety and effectiveness of non-myeloablative allogeneic HSCT for the treatment of thalassemia major. The ability to draw conclusions regarding improved health outcomes is limited by small patient populations, heterogeneous conditioning regimens, and study design. Contraindications to Transplantation Many factors affect the outcome of tissue transplantation; the selection process is designed to obtain the best result for each individual. Overall health, age, and disease stage are extremely important considerations in Page 4 of 9

5 evaluating candidates. Relative contraindications to hematopoietic stem-cell transplantation (HSCT) include, but are not limited to: poor cardiac function (ejection fraction < 45%) poor liver function (bilirubin > 2.0mg/dl and transaminases greater than two times normal) poor renal function (creatinine clearance < 50ml/min poor pulmonary function [diffusion capacity (DLCO) < 60% of predicted] presence of human immunodeficiency virus OR an active form of any ONE of the following: hepatitis B virus (HBV) hepatitis C virus (HCV) human T-cell lymphotropic virus (HTLV)-1 Karnofsky rating < 60% and/or Eastern Cooperative Oncology Group (ECOG) performance status > 2 Professional Societies/Organizations National Marrow Donor Program (NMDP): The NMDP ( ) lists hemoglobinopathies, including sickle cell disease (SCD) and thalassemia major, as diseases which are treatable by allogeneic hematopoietic stemcell transplantation (HSCT). National Heart, Lung and Blood Institute (NHLBI): The NHLBI (2002) notes that bone marrow transplantation may offer a cure for a small number of people with sickle cell anemia. The NHLBI also noted that it is usually used only for younger individuals with severe sickle cell anemia, but the decision is made on a case-by-case basis. Regarding thalassemia, the NHLBI (2012) notes that stem cell transplantation is the only treatment that can cure thalassemia; only a small number of people who have severe thalassemias are able to find a good donor match and have the risky procedure. Use Outside of the US: No relevant information. Summary Although data are limited, the published peer-reviewed scientific literature supports the safety and effectiveness of myeloablative allogeneic hematopoietic stem-cell transplantation (HSCT) for the treatment of selected children and young adults with sickle cell disease (SCD) and thalassemia major. Further, use of allogeneic HSCT for these indications is supported by several professional organizations. However, there are insufficient data in the published peer-reviewed scientific literature to support the safety and effectiveness of myeloablative allogeneic HSCT for the treatment of adults with SCD or thalassemia major. Additionally, there is insufficient evidence to support the effectiveness of non-myeloablative allogeneic HSCT for the treatment of SCD and thalassemia major in children or adults. Patient study populations are small and do not allow the ability to determine if health outcomes are improved. Further, professional society/organization support are lacking in published consensus documents. Although a subject of clinical study, the role of HSCT for these indications has not yet been established. Coding/Billing Information Note: 1) This list of codes may not be all-inclusive. 2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement Covered when medically necessary when used to report myeloablative allogeneic bone marrow or blood-derived stem cell procedures for sickle cell disease or thalassemia major in children or young adults: CPT * Description Codes Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic Transplant preparation of hematopoietic progenitor cells; cryopreservation and Page 5 of 9

6 storage Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing, per donor Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, with washing, per donor Transplant preparation of hematopoietic progenitor cells; specific cell depletion within harvest, T-cell depletion Transplant preparation of hematopoietic progenitor cells; red blood cell removal Transplant preparation of hematopoietic progenitor cells; platelet depletion Transplant preparation of hematopoietic progenitor cells; plasma (volume) depletion Transplant preparation of hematopoietic progenitor cells; cell concentration in plasma, mononuclear, or buffy coat layer Bone marrow harvesting for transplantation; allogeneic Hematopoietic progenitor cell (HPC); allogeneic transplantation, per donor Allogeneic lymphocyte infusions HCPCS Codes S2140 S2142 S2150 Description Cord blood harvesting for transplantation, allogeneic Cord blood-derived stem-cell transplantation, allogeneic Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days or of pre-and post-transplant care in the global definition *Current Procedural Terminology (CPT ) 2013 American Medical Association: Chicago, IL. References 1. American Association for Clinical Chemistry. Lab tests online: hemoglobin variants American Association for Clinical Chemistry. Updated 2013 July 21. Accessed Jun 4, Available at URL address: 2. Bernaudin F, Socie G, Kuentz M, Chevret S, Duvall M, Bertrand Y, et al. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood Oct 1;110(7): Epub 2007 Jul Bhatia M, Walters MC. Hematopoietic stem cell transplantation for thalassemia and sickle cell disease: past, present and future. Bone Marrow Transplant Jan;42(2): Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, Brodsky RA. HLAhaploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood Nov 22;120(22): Accessed Jun 4, Available at URL address: 5. Borgna-Pignatti C, Galanello R. Thalassemias and related disorders: quantitative disorders of hemoglobin synthesis. In: Greer JP, Foester J, Rodgers GM, Paraskevas F, Glader B, Arber DA, Means RT, editors. Wintrobe s Clinical Hematology, 13 th ed. Philadelphia (PA): Lippincott Williams & Wilkins, Dallas MH, Triplett B, Shook DR, Hartford C, Srinivasan A, Laver J, et al. Long-term outcome and evaluation of organ function in pediatric patients undergoing haploidentical and matched related Page 6 of 9

7 hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant May;19(5): Epub 2013 Feb DeBaun MR, Frei-Jones M, Vichinsky E. Hemoglobinopathies. In: Kleigman RM, Stanton BF, St. Geme III JW, Schor NF, Behrman RE, editors. Nelson textbook of pediatrics, 19 th ed. Philadelphia (PA): Saunders Elsevier; Hankins J, Wang WC. Sickle Cell Anemia and Other Sickling Syndromes. In: Greer JP, Foester J, Rodgers GM, Paraskevas F, Glader B, Arber DA, Means RT, editors. Wintrobe s Clinical Hematology, 13 th ed. Philadelphia (PA): Lippincott Williams & Wilkins, Hebbel RP. Pathobiology of sickle cell disease. In: Hoffman R, Benz, Jr. EJ, Silberstein LE, Heslop HE, Weitz JI, Anastasi J, editors. Hematology: basic principles and practice, 6 th ed. Orlando: Churchill Livingstone; Holstein SA, Hohl RJ. Thalassemia. In: Bope ET, Kellerman R, editors. Conn s current therapy 2014, 1st ed. Philadelphia: Saunders Elsevier Hongeng S, Pakasama S, Chaisiripoomere W, Ungkanont A, Jootar S. Nonmyeloablative stem cell transplantation with a haploidentical donor in a class 3 Lucarelli severe thalassemia patient. Bone Marrow Transplant Aug;34(3): Hongeng S, Pakakasama S, Chuansumrit A, Sirachainan N, Kitpoka P, Udomsubpayakul U, et al. Outcomes of transplantation with related- and unrelated-donor stem cells in children with severe thalassemia. Biol Blood Marrow Transplant Jun;12(6): Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine and rabbit anti-thymocyte globulin. Bone Marrow transplant Jan;35(2): Horwitz ME, Spasojevic I, Morris A, Telen M, Essell J, Gasparetto C, et al. Fludarabine-based nonmyeloablative stem cell transplantation for sickle cell disease with and without renal failure: clinical outcome and pharmacokinetics. Biol Blood Marrow Transplant Dec;13(12): Iannone R, Casella JF, Fuch EJ, Chen AR, Jones RJ, Woolfrey A. Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia. Biol Blood Marrow Transplant Aug;9(8): Jaing TH, Hung IJ, Yang CP, Chen SH, Chung HT, Tsay PK, Wen YC. Unrelated cord blood transplantation for thalassaemia: a single-institution experience of 35 patients. Bone Marrow Transplant Jan;47(1): Jaing TH, Hung IJ, Yang CP, Chen SH, Sun CF, Chow R. Rapid and complete donor chimerism after unrelated mismatched cord blood transplantation in 5 children with beta-thalassemia major. Biol Blood Marrow Transplant May;11(5): Krishnamurti L, Karbanda S, Biernacki MA, Zhang W, Baker KS, Wagner JE, et al. Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant Nov;14(11): La Nasa G, Caocci G, Argiolu F, Giardini C, Locatelli F, Vacca A, et al. Unrelated donor stem cell transplantation in adult patients with thalassemia. Bone Marrow Transplant Dec;36(11): Locatelli F, De Stephano P. Innovative approaches to hematopoietic stem cell transplantation for patients with thalassemia. Haematologica Dec;90(12): Page 7 of 9

8 21. Locatelli F, Pagliara D. Allogeneic hematopoietic stem cell transplantation in children with sickle cell disease. Pediatr Blood Cancer Aug;59(2): Epub 2012 Apr National Heart, Lung and Blood Institute. The management of sickle cell disease, 4 th ed. NIH Publication Jun Accessed 2014 Jun 4. Available at URL address: National Heart, Lung and Blood Institute. What are thalassemias? Accessed June 4, Available at URL address: National Institutes of Health, Genetics Home Reference: beta thalassemia. Updated 2014 Jun 2. Accessed 2014 Jun 4. Available at URL address: National Institutes of Health, National Human Genome Research Institute. Learning about thalassemia. Updated 2013 Dec 27. Accessed 2014 Jun 4. Available at URL address: National Marrow Donor Program. Physician resources: diseases treatable by hematopoietic cell transplant National Marrow Donor Program. Accessed 2014 Jun 4. Available at URL address: Novelli EM, Gladwin MT, Krishmnamurti L. Sickle cell disease. In: Bope ET, Kellerman R, editors. In: Conn s current therapy 2014, 1st ed. Philadelphia: Saunders Elsevier Oringanje C, Nemecek E, Oniyangi O. Hematopoietic stem cell transplantation for people with sickle cell disease. Cochrane Database Syst Review May 31;(5):CD Panepinto JA, Walters MC, Carreras J, Marsh J, Bredeson CN, Gayle RP, et al. Matched-related donor transplantation for sickle cell disease: report from the Center for International Blood and Transplant Research. Br J Haematol Jun;137(5): Epub 2007 Apr Resnick IB, Aker M, Tsirigotis P, Shapira MY, Abdul-Hai A, Bitan M, et al. Allogeneic stem cell transplantation from matched related and unrelated donors in thalassemia major patients using a reduced toxicity fludarabine-based regimen. Bone Marrow Transplant Nov;40(10): Epub 2007 Sep Ruggeri A, Eapen M, Scaravadou A, Cairo MS, Bhatia M, Kurtzberg J, et al., Umbilical cord blood transplantation for children with thalassemia and sickle cell disease. Biol Blood Marrow Transplant Sep;17(9): Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med Sep 15;353(11): Sevilla J, Fernandez-Plaza S, Diaz MA, Madero L, Paediatric Working Party of the EBMT. Hematopoietic transplantation for bone marrow failure syndromes and thalassemia. Bone Marrow Transplant Mar;35 Suppl 1:S Sickle Cell Disease Association of America (SCDAA). About sickle cell disease. Copyright 2014 Sickle Cell Disease Association of America, Inc. Accessed 2014 Jun 4. Available at URL address: Smiers FJ, Krishnamurti L, Lucarelli G. Hematopoietic stem cell transplantation for hemoglobinapathies: current practice and emerging trends. Pediatr Clin North Am Feb;57(1): Sodani P, Isgro A, Gaziev J, Paciaroni K, Marziali M, Simone MD, et al. T-cell depleted hlahaploidentical stem cell transplantation in thalassemia young patients. Pediatr Rep Jun 2;3 Suppl 2:e13. Page 8 of 9

9 37. Thompson AA. Advances in the management of sickle cell disease. Pediatr Blood Cancer May 1;46(5): van Besien K, Bartholomew A, Stock W, Peace D, Devine S, Sher D, et al. Fludarabine-based conditioning for allogeneic transplantation in adults with sickle cell disease. Bone Marrow Transplant Aug;26(4): Velardi A, Locatelli F. Hematopoietic stem cell transplantation. In: Kleigman RM, Stanton BF, St. Geme III JW, Schor NF, Behrman RE, editors. Nelson textbook of pediatrics, 19 th ed. Philadelphia: Saunders; Walters MC, Quirolo L, Trachtenberg ET, Edwards S, Hale L, Lee J, et al. Sibling donor cord blood transplantation for thalassemia major: Experience of the Sibling Donor Cord Blood Program. Ann N Y Acad Sci. 2005;1054: Yesilipek MA. Stem cell transplantation in hemoglobinopathies. Hemoglobin. 2007;31(2): The registered marks "Cigna" and the "Tree of Life" logo are owned by Cigna Intellectual Property, Inc., licensed for use by Cigna Corporation and its operating subsidiaries. All products and services are provided by or through such operating subsidiaries and not by Cigna Corporation. Such operating subsidiaries include Connecticut General Life Insurance Company, Cigna Health and Life Insurance Company, Cigna Behavioral Health, Inc., Cigna Health Management, Inc., and HMO or service company subsidiaries of Cigna Health Corporation. Page 9 of 9